Novel hormonal therapies (NHTs) are a group of medicines commonly used to intensify some kinds of prostate cancer treatment. They are also called androgen receptor pathway inhibitors (ARPIs).For some men with prostate cancer that has spread (metastasized), NHTs are added to treatment with androgen deprivation therapy (ADT).
ADT has been an effective treatment for advanced (metastatic) prostate cancer for more than 50 years. ADT lowers the amount of testosterone in the body. Because prostate cancer often depends on testosterone and other male hormones called androgens to grow, lowering these hormones can slow the cancer.
But doctors have learned that ADT alone is often not enough to control advanced prostate cancer. As a result, treatment is often intensified by adding another type of treatment to ADT.
Chemotherapy was one of the first types of medicine used to intensify treatment. NHTs are a newer method. NHTs work in different ways, but they all target the pathways that prostate cancer uses to grow in response to testosterone and other androgens. Although each medicine works differently, any of them may be an important part of treatment for some men with advanced prostate cancer.
In this article, you’ll learn about these four NHTs:
Abiraterone Acetate
Abiraterone acetate was the first NHT to show a proven benefit for men with advanced prostate cancer. Unlike some other NHTs that block the action of testosterone, abiraterone works by reducing the amount of testosterone and other androgens that the body makes. It blocks an enzyme that the body needs to make testosterone and related hormones. This enzyme is found in:
- The testicles
- The adrenal glands
- Prostate cancer cells
Because this affects the making of other hormones that the body needs, abiraterone is given with a corticosteroid, such as prednisone or prednisolone. This helps prevent hormone problems caused by abiraterone.
Who Can Take Abiraterone?
Abiraterone is approved for some men with either of these:
- Metastatic castration-sensitive prostate cancer (mCSPC). Abiraterone is started at the same time as, or shortly after, ADT.
- Metastatic castration-resistant prostate cancer (mCRPC). This is cancer that keeps growing despite low testosterone levels from ADT.
Men can take abiraterone for mCRPC whether or not they have had chemotherapy before.
How Well Does Abiraterone Work?
Clinical trials have shown that adding abiraterone to ADT can help men with advanced prostate cancer live longer. For example:
- In the LATITUDE and STAMPEDE clinical trials, adding abiraterone to ADT for men with mCSPC reduced the risk of death by 38% and 37%, respectively, compared with ADT alone.
- In the COU-AA-302 clinical trial, abiraterone reduced the risk of death by 25% in men with mCRPC who did not have chemotherapy.
- In the COU-AA-301 clinical trial, abiraterone reduced the risk of death by 35% in men with mCRPC who did have chemotherapy.
Who Should Not Take Abiraterone?
Abiraterone is not right for every person. You should not take abiraterone if you have had an allergic or severe hypersensitivity reaction to the medicine.
Abiraterone should be used with caution if you have any of these:
- Severe liver disease
- Too much mineralocorticoid
- Not enough adrenocorticoid
- Severe heart disease
- Low blood potassium (hypokalemia)
Your doctor will look at your medical history and may do blood tests before and during treatment.
How Do You Take Abiraterone?
Abiraterone is usually taken as four tablets once a day. You take it:
- On an empty stomach
- At least 1 hour before eating, or at least 2 hours after eating
You will also take a corticosteroid, such as prednisone, either once or twice a day, depending on your treatment plan.
Medicine Interactions with Abiraterone
Abiraterone can interact with other medicines because it’s processed by enzymes in the liver. Some types of medicines can affect these liver enzymes. This means they can increase or decrease the amount of abiraterone in your body. This includes medicines such as:
- Atazanavir
- Carbamazepine
- Clarithromycin
- Indinavir
- Itraconazole
- Ketoconazole
- Nefazodone
- Nelfinavir
- Phenobarbital
- Phenytoin
- Rifabutin
- Rifampin
- Rifapentine
- Ritonavir
- Saquinavir
- Telithromycin
- Voriconazole
Make sure your doctor knows about all prescription medicines, over-the-counter medicines, vitamins, and supplements you take. A cancer pharmacist can help review your medicines for possible interactions.
What Are Possible Side Effects of Abiraterone?
Possible side effects include:
- High blood pressure
- Low blood potassium
- Swelling of the hands, feet, ankles, or legs
- Urinary tract infections
- Diarrhea
- Rash
- Increased liver enzymes on blood tests
Other side effects are possible. Your healthcare team will monitor you during treatment and can help manage side effects if they occur.
Enzalutamide
Enzalutamide works differently from abiraterone. Rather than preventing the body from making testosterone, it blocks testosterone from activating the androgen receptor on prostate cancer cells.
The androgen receptor acts like an "on switch" for signals that help prostate cancer cells grow. Enzalutamide interferes with this process in several ways.
It can:
- Prevent testosterone from attaching to the androgen receptor
- Prevent the receptor from being activated
- Prevent the receptor from moving into the cell's nucleus, where it can affect DNA and stimulate cancer growth
Who Can Take Enzalutamide?
Enzalutamide is approved for some men with any of these:
- High-risk non-metastatic biochemical recurrence. Enzalutamide can be used by itself or in combination with ADT.
- Metastatic castration-sensitive prostate cancer (mCSPC). Enzalutamide is started at the same time as, or shortly after, ADT.
- Nonmetastatic castration-resistant prostate cancer (nmCRPC). Enzalutamide may be started when the PSA is rising despite low testosterone levels from ADT, even though imaging does not show cancer that has spread.
- Metastatic castration-resistant prostate cancer (mCRPC). Enzalutamide is used when the cancer progresses despite ADT.
Men can take enzalutamide for mCRPC whether or not they have had chemotherapy before.
How Well Does Enzalutamide Work?
Clinical trials have shown benefits from enzalutamide. For example:
- In the EMBARK clinical trial, patients with high-risk non-metastatic biochemical recurrence had a reduced risk of metastatic disease by 58% when receiving enzalutamide + ADT, and 37% for those receiving enzalutamide alone. For patients receiving enzalutamide + ADT, EMBARK also showed a reduced risk of death of 40%.
- In the ENZAMET and ARCHES clinical trials, adding enzalutamide to treatment for mCSPC reduced the risk of death by 33% and 34%, respectively, compared with ADT-based treatment without enzalutamide.
- In the PROSPER clinical trial, enzalutamide reduced the risk of metastatic disease by 72% in men with nmCRPC. It also reduced the risk of death by 31%.
- In men with mCRPC, enzalutamide reduced the risk of death by 37% in the AFFIRM clincial trial among men who had received chemotherapy and by 29% in the PREVAIL clinical trial among men who had not.
Who Should Not Take Enzalutamide?
Enzalutamide may not be right for people with some medical conditions. Tell your doctor if you have a history of any of these:
- Seizures
- Stroke
- Brain injury
- Cancer that has spread to the brain
You should not take enzalutamide if you have had an allergic or severe hypersensitivity reaction to the medicine.
Also tell your doctor if you have heart or kidney problems.
How Do You Take Enzalutamide?
Enzalutamide is usually taken as four tablets once a day. You take the tablets at the same time each day. They can be taken with or without food.
Medicine Interactions with Enzalutamide
Enzalutamide can affect the way your liver processes other medicines. This means it can interact with many common medicines.
Tell your doctor about all the medicines you take, especially if you take medicines for any of these:
- Anxiety
- Epilepsy
- Gout
- Heart problems
- High blood pressure
- High cholesterol
- Pain
- Schizophrenia
- Sleep problems
- Thyroid problems
A cancer pharmacist can help review your medicines for possible interactions.
What Are Possible Side Effects of Enzalutamide?
Common side effects include:
- Severe tiredness (fatigue)
- Hot flashes
- Breast tenderness or swelling
- Muscle pain
- Diarrhea
- Constipation
- Increased risk of falls and broken bones (fractures)
The medicine has a small increased risk of seizures. The risk of seizures may be higher if you:
- Have had seizures before
- Drink a lot of alcohol
- Have had a stroke or brain injury
- Have cancer that has spread to the brain
- Take medicines that can increase the risk of seizures
Other side effects are possible. Your healthcare team will monitor you during treatment.
Apalutamide
Apalutamide is another NHT that blocks the action of testosterone. Like enzalutamide, it works by interfering with the androgen receptor. This prevents prostate cancer cells from getting signals that tell them to grow. Apalutamide can:
- Block movement of the androgen receptor within the cell
- Prevent the receptor from interacting with DNA
- Block signals produced by the receptor inside the cell
Who Can Take Apalutamide?
Apalutamide is approved for some men with either of these:
- Nonmetastatic castration-resistant prostate cancer (nmCRPC)
- Metastatic castration-sensitive prostate cancer (mCSPC)
For nmCRPC, apalutamide may be started when the PSA is rising despite low testosterone levels from ADT, but imaging does not show metastatic disease.
How Well Does Apalutamide Work?
In the SPARTAN clinical trial, apalutamide reduced the risk of developing metastatic disease by 72% in men with nmCRPC. It also reduced the risk of death by 22%.
In the TITAN clinical trial, adding apalutamide to ADT reduced the risk of death for men with mCSPC by 35% compared with ADT alone.
Who Should Not Take Apalutamide?
People with cancer that has spread to the brain may not be good candidates for apalutamide. You should not take apalutamide if you have had an allergic or severe hypersensitivity reaction to it.
Tell your doctor if you have:
- A history of seizures
- A history of stroke
- A previous brain injury
- Cancer that has spread to the brain
- Heart or kidney problems
How Do You Take Apalutamide?
Apalutamide is usually taken as four tablets once a day. You take the tablets at approximately the same time each day. They can be taken with or without food.
Apalutamide can interact with other medicines, so make sure your doctor knows about everything you take. A cancer pharmacist can help review your medicines for possible interactions.
What Are Possible Side Effects of Apalutamide?
Common side effects include:
- Severe tiredness (fatigue)
- High blood pressure
- Nausea
- Diarrhea
- Rash
- Increased risk of falls and broken bones (fractures)
Apalutamide can also affect thyroid function. Some people may need to take medicine to replace thyroid hormones.
The medicine has a small increased risk of seizures. The risk of seizures may be higher if you:
- Have had seizures before
- Drink a lot of alcohol
- Have had a stroke or brain injury
- Have cancer that has spread to the brain
- Take medicines that can increase the risk of seizures
Other side effects are possible. Your healthcare team will monitor you during treatment.
Darolutamide
Darolutamide is another NHT that blocks the androgen receptor. Like enzalutamide and apalutamide, it interferes with the androgen receptor's ability to send signals that help prostate cancer cells grow. Darolutamide is different from these medicines because it has low penetration into the brain and in clinical trials was associated with fewer of these side effects.
This medicine can:
- Block movement of the androgen receptor within the cell
- Prevent the receptor from interacting with DNA
- Block the receptor from making signals inside the cell
Who Can Take Darolutamide?
Darolutamide is approved for some men with either of these:
- Nonmetastatic castration-resistant prostate cancer (nmCRPC)
- Metastatic castration-sensitive prostate cancer (mCSPC) when used with ADT +/- docetaxel chemotherapy
Darolutamide is also approved as part of a triplet treatment for some men with mCSPC. This treatment combines:
- ADT
- Docetaxel chemotherapy
- Darolutamide
How Well Does Darolutamide Work?
For men with nmCRPC, the ARAMIS clinical trial showed that darolutamide reduced the risk of developing metastatic disease by 59%. It also reduced the risk of death by 31%.
In the ARASENS clinical trial, the combination of ADT, docetaxel chemotherapy, and darolutamide reduced the risk of death by 32% compared with ADT and docetaxel alone. The FDA approved this combination in 2022.
In the ARANOTE clinical trial, the combination of ADT and darolutamide reduced the risk of radiographic progression or death by 46% versus placebo + ADT. The FDA approved this combination in June 2025.
Who Should Not Take Darolutamide?
You should not take darolutamide if you have had an allergic or severe hypersensitivity reaction to it.
Tell your doctor if you have:
- Heart problems
- Liver problems
- Kidney problems
Your doctor may adjust your dose if you have certain liver or kidney problems.
How Do You Take Darolutamide?
Darolutamide is taken as two tablets two times a day. You take the tablets at the same times each day. They can be taken with or without food.
Darolutamide can interact with other medicines. Make sure your doctor knows about all the prescription medicines, over-the-counter medicines, vitamins, and supplements you take. A cancer pharmacist can help review your medicines for possible interactions.
What Are Possible Side Effects of Darolutamide?
Common (and often mild) side effects include:
- Tiredness (fatigue)
- Pain in the arms or legs
- Rash
In some cases, darolutamide may also:
- Increase the risk of heart disease
- Affect liver function blood tests
Unlike enzalutamide and apalutamide, darolutamide does not increase the risk of seizures, falls, or fractures.Other side effects are possible. Your healthcare team will monitor you during treatment.
Choosing a Novel Hormonal Therapy
There are several NHT options for advanced prostate cancer. The best choice for you depends on many factors, including:
- If your cancer has spread
- If your cancer is still responding to hormone therapy
- Which treatments you have already received
- Your other health conditions
- The medicines you take
- Your risk of side effects
- Your preferences and treatment goals
Your healthcare team can help you compare the potential benefits and risks of each treatment.
Be sure to tell your healthcare team about every medicine, vitamin, and supplement you take. Because NHTs can interact with other medicines, a cancer pharmacist can help review your medicines for possible interactions.
As with any cancer treatment, discuss your individual situation and treatment options with your doctor.
